Project Summary Abstract Recent studies indicate that physical exercise exerts benefits on cognitive health, at least in part, through effects on hippocampal neurogenesis. Other lines of investigation indicate that physical exercise is essential for the optimum health, differentiation, and tissue integration of therapeutic stem cell implants. The current proposal is focused on assessing the potential ability of this compound, BCI-838, to mimic and/or potentiate the proneurogenic and procognitive effects of physical exercise when studied in either the ?A? oligomer only? model and a MAPT P301L model of tauopathy. Developing effective treatments for both cerebral amyloidosis and cerebral tauopathy is considered to be within the mission of the RRD section of VA ORD. In order to assess the potential ability of a Group II mGluR antagonist (BCI-838) to mimic and/or potentiate the proneurogenic and procognitive effects of physical exercise, Dutch mutant APPE693Q ?A? oligomer only? mice and MAPTP301L tauopathy mice will be undergo 3 mo treatment with either (i) voluntary exercise only, (ii) proneurogenic drug treatment only (Group II mGluR antagonist, BCI-838), or (iii) both. The treated mice will undergo behavioral tests to assess their cognitive performance and anxiety levels. After finishing behavioral tests, their hippocampi will be used for an assay of neurogenesis and RNAseq assay of transcriptome. Because of the implication of BDNF in exercise-stimulated neurogenesis, we will also analyze each type of mouse (wildtype, A? oligomer, tauopathy) for drug or exercise response after crossing with either (i) a floxed/conditional Ntrk2(also known as trkB)-/- mouse or (iii) a floxed/conditional Ntrk2F616A. The mouse is engineered such that all trkB signaling is acutely abolished following oral treatment with the drug NMPP1. Together, the floxed trkB-/- and the floxed Ntrk2F616A provide scenarios of chronic and acute deficiencies, respectively, of trkB signaling. The floxed Ntrk2F616Awill also ensure that trkB signaling is abrogated in all relevant cells. A third option for depleting the hippocampus of trkB is the injection of AAV-trkB siRNA. The results of these studies could inform a novel approach to neurodegenerative diseases aimed at stimulating hippocampal neurogenesis, through the use of physical exercise, mGluR antagonists, trkB modulators, or some combination of two or more of these. Such an approach could address a major unmet need among the over 500,000 Veterans now living with dementia. This figure will only increase in the coming decades, and, if unchecked, threatens economies worldwide.